4 October 2012. A new study published online September 19 in Nature, led by Paul Phillips of the University of Washington in Seattle, finds that the neuropeptide corticotropin-releasing factor (CRF) increases dopamine release in the nucleus accumbens, but that this effect is abolished by exposure to severe stress. Moreover, while CRF is positively motivating under normal circumstances, stress exposure results in CRF becoming aversive—a reversal of its action. This change in the emotional response to a stressor is reminiscent of major depressive disorder symptomatology and suggests a potential mechanism by which the affective shift in this illness occurs.

CRF is a neuropeptide that is involved in the body’s stress response system, the hypothalamic pituitary-adrenal (HPA) axis. CRF is released in response to stress, and stimulates the release of adenocorticotropic hormone that in turn stimulates cortisol release from the adrenal gland. Cortisol’s actions are widespread, ranging from metabolism to behavior, and allow the body to respond to the stress (Nestler et al., 2002).

Stress, the HPA axis, and CRF have all been implicated in several neuropsychiatric illnesses, most notably major depressive disorder (MDD). Stress is known to precipitate MDD, and MDD subjects exhibit a hyperactive HPA axis and increased levels of CRF in cerebrospinal fluid (Keller et al., 2006). Stress is relevant to schizophrenia as well, as it exacerbates symptoms and has even been implicated in the etiology of the illness (Corcoran et al., 2003).

The nucleus accumbens, situated at the interface between limbic, cognitive, and motor circuits, mediates a variety of stress responses and has been implicated in MDD (Nestler et al., 2002). It is also involved in behaviors such as social bonding and motivation that are thought to be dopamine dependent (Aragona et al., 2006). Since CRF also affects neurotransmission through its receptors CRFR1 and CRFR2, Phillips and colleagues examined CRF’s role on dopamine function in the nucleus accumbens.

In the current paper, first author Julia Lemos and colleagues found that CRF administration in the nucleus accumbens produced an increase in dopamine release, an effect mediated through CRFR1 and CRFR2. Next, the researchers turned to the behavioral effects of CRF by examining conditioned place preference after injection of CRF into the nucleus accumbens. Consistent with an increase in dopamine release, animals strongly preferred the CRF-paired context over the vehicle-paired one, indicating that CRF is a positive stimulus. This place preference was dependent on an increase in dopamine, as administration of 6-hydroxydopamine, a neurotoxin that kills dopamine neurons, abolished the effect. CRF was found to have similar positive effect on novel object exploration.

However, after exposure to two days of severe stress induced by a Porsolt swim paradigm, the ability of CRF to increase dopamine release in the nucleus accumbens disappeared. In fact, this effect persisted for at least 90 days following stress exposure, during which time the mice exhibited a depression-like phenotype. Results from the conditioned place preference task suggested that CRF was now aversive to the animals that underwent swim stress, as they spent significantly less time in the CRF-paired chamber than the vehicle-paired one. Stress also eliminated novel object exploration.

These results suggest a mechanism by which stress impairs the regulation of dopamine neurotransmission in the nucleus accumbens, and as noted by the authors, “provide a neurobiological mechanism for the affective shift from engagement of the environment to withdrawal following severe stress, central to the manifestation of major depressive disorder.”—Allison A. Curley